1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane

Endpoint summary

Description of key information

There are no acute toxicity data available for the registered substance. However, reliable data are available for a structural analogue. The key study for acute oral toxicity was read-across from 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8) and reported an LD50 value of >2000 mg/kg bw in rat. The study was conducted according to a protocol equivalent to the now-deleted OECD 401 Test Guideline but not in compliance with GLP (Haruna, 2001, reliability 2).  

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 30 2001 - July 23 2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study was not conducted in compliance with GLP.

Qualifier:

according to guideline

Guideline:

other: Guidance on Safety Assessment of New Cosmetics (Japan Cosmetic Industry Association, technical materials No.92, 1991

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crj:CD(SD)IGS

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Atsugi Breeding Center, Charles River Japan Inc.
- Age at study initiation:6 weeks
- Weight at study initiation: male 193-212 g, female 131-151 g
- Fasting period before study: ca. 18 hours
- Housing: Individually housed, in stainless steel bracket cages for rats
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): minimum 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 100 or 200 mg/mL


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: According to the Guidance on Safety Assessment of New Cosmetics, 2000 mg/kg was set for the high dose group, 1000 mg/kg for the low dose group, and olive oil for the control group.

Doses:

vehicle at 0 mg/kg, 1000 and 2000 mg/kg

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for clinical signs and mortality at 15, 30 minutes, 1, 3 and 6 hours after treatment on the day of treatment and thereafter once daily. Animals were weighed on the day of treatment and on days 2, 3, 4, 8, 11 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other: The body surface and the intracranial, intrathoracic and intra-abdominal organs were macroscopically examined. Histopathological examination was not performed because necropsy did not reveal any abnormal changes.

Statistics:

The body weight measurements obtained in the study were averaged and standard deviation was calculated for each group, which were analysed for homogeneity of variance by F-test. Since the results showed homogenous variance, Student t-test was performed. There was no statistical significance noted.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred through the observation period in either males or females in all the groups including the control group in response to test article administration.

Clinical signs:

other: No clinical signs caused by the test substance were observed. Watery diarrhoea was observed in males and females in all groups, which ceased by day 2 of treatment, after which no special changes were observed.

Gross pathology:

There were no remarkable findings at necropsy in any group of animals.

Other findings:

None reported.

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Not classified according to Regulation (EC) No 1272/2008

Conclusions:

An LD50 value of >2000 mg/kg bw in rats of both sexes is reported in a study equivalent to the now-deleted OECD 401 Guideline, which was not GLP compliant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

An oral LD₅₀ value of >2000 mg/kg bw in rats of both sexes is reported in a GLP compliant study conducted according to a Japanese guideline equivalent to the now-deleted OECD 401 Test Guideline (Haruna, 2001, reliability 2). No deaths occurred through the observation period in either males or females in any of the groups including the control group in response to test article administration. No clinical signs in response to the test substance were observed. Watery diarrhoea was observed in males and females in all groups including control group, which ceased by day 2 of treatment, after which no special changes were observed. During the observation period, there was no statistical difference in body weight measurements between the groups. The body weight of all animals increased favourably. There were no remarkable findings at necropsy in any of the animals.

Read-across justification

There are no available measured data for 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane(CAS 3555-47-3) for acute toxicity. This document describes the analogue approach for fulfilling this endpoint by read-across from a source substance1,1,1,3,5,5,5 -heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), according to the Read-across Assessment Framework (RAAF)[1].

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 5.6.4) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 1: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF¹

AE A.1	Characterisation of source substance
AE A.2	Link of structural similarity and differences with the proposed Prediction
AE A.3	Reliability and adequacy of the source study
AE 2.1	Compounds the test organism is exposed to
AE 2.2	Common underlying mechanism, qualitative aspects
AE 2.3	Common underlying mechanism, quantitative aspects
AE 2.4	Exposure to other compounds than to those linked to the prediction
AE 2.5	Occurrence of other effects than covered by the hypothesis and Justification
AE A.4	Bias that influences the prediction

1.       AE A.1 Identity and characterisation of the source substance

The source substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), is a tertiary branched methylated siloxane structure of four Si atoms. The longest siloxane chain consists of three silicon atoms and two oxygen atoms, with a Si-O branch on the central silicon atom in the chain. The silicon atoms are fully substituted by methyl groups. Hydrolysis half-life values of 3.6 h at pH 4, 630 h at pH 7, 5.3 h at pH 9 and 20-25°C were obtained using an accepted calculation method.  

At pH 2 (the known pH of the stomach), the calculated hydrolysis rate is approximately 2.2 minutes. Reaction rate increases with temperature therefore hydrolysis will be faster at physiologically relevant temperatures compared to standard laboratory conditions. Thus, at 37.5°C and pH 2 (relevant for conditions in the stomach following oral exposure), the hydrolysis half- life is calculated as 0.013 hours (48 seconds). The products of hydrolysis are trimethylsilanol (3 moles) and methylsilanetriol (1 moles).

The source substance has log Kow of 8.2 at 20°C (QSAR), water solubility of 0.00189 mg/l at 23°C (QSAR) and vapour pressure of 210 Pa at 25°C (OECD 104).

2.       AE A.2 Link of structural similarities and differences with the proposed prediction

The registration substance, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), and the read-across substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), are structurally similar and are members of an analogue group of linear and branched siloxanes.

1,1,1,3,5,5,5-Heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8) is a is a tertiary branched methylated siloxane structure of four Si atoms, while 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3) is a quaternary branched methylated siloxane structure of five Si atoms. In both substances the longest siloxane chain consists of three silicon atoms and two oxygen atoms. The source substance has a Si-O branch on the central silicon atom in the chain, while the target substance has two oxygen atoms, with two Si-O branches on the central silicon atom in the chain. The silicon atoms are fully substituted by methyl groups.

The Si-containing hydrolysis product for both the target and source substance is trimethylsilanol. (Poly)silicic acid is the non-Si hydrolysis product for the target substance and methylsilanetriol for the source substance. These two substances both hydrolyse in similar rate to 4 moles or 3 moles of trimethylsilanol.

Table 2: Physico-chemical properties

Property		Target substance		Source substance
Substance name		1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane		1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane
CAS number		3555-47-3		17928-28-8
Hydrolysis half-life at pH 2 and 37.5 °C		25 seconds		48 seconds
Silanol hydrolysis product		trimethylsilanol		trimethylsilanol
Non-Si hydrolysis product		(poly)silicic acid		methylsilanetriol
LogKow value		9at 20°C (QSAR)		8.2 at 20°C (QSAR)
Vapour pressure		15 Pa at   25°C (measured)		210 Pa at 25°C (OECD 104)
Water solubility		0.1507 µg/l at 20-25°C (measured)		0.00189 mg/l at 23°C (QSAR)

3.       AE A.3 Reliability and adequacy of the source study

The key study for acute oral toxicity reports an LD50 value of >2000 mg/kg bw in rat, conducted according to a protocol equivalent to the now-deleted OECD 401 Test Guideline but not in compliance with GLP (Haruna 2001).  

No deaths occurred through the observation period in either males or females in any of the groups including the control group in response to test article administration. No clinical signs in response to the test substance were observed. Watery diarrhoea was observed in males and females in all groups including control group, which ceased by day 2 of treatment, after which no special changes were observed. During the observation period, there was no statistical difference in body weight measurements between the groups. The body weight of all animals increased favourably. There were no remarkable findings at necropsy in any of the animals.

4.       AE A.4 Bias that influences the prediction

Data on the source substance 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8) were read-across to the registered (target) substance 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3). The source substance and the target substance have similar chemical structure and physico-chemical properties. Both substances hydrolyse at similar rate to the same Si-containing hydrolysis product, trimethylsilanol. However, the non-silanol hydrolysis products are different, (poly)silicic acid and methylsilanetriol for the target and source substance, respectively. Despite that, their toxicological properties are expected to be similar, with similar acute toxicity. No other data for relevant substances were available. These substances are the closest structural analogues to the target substance; other siloxanes show consistent results.

5.       AE A.2.1 Compounds the test organism is exposed to

Both substances hydrolyse very rapidly in contact with water under conditions relevant for oral exposure.   Therefore, the test organism is mainly exposed to their hydrolysis products, trimethylsilanol, (poly)silicic acid and methylsilanetriol.  The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The three substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. No alert for acute toxicity was detected by OECD QSAR Toolbox v.4.1.  

The acute toxicity of (poly)silicic acid is well established. No classification for acute oral toxicity has been assigned to the substance.

6.       AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

No toxicity data are available for the target substance 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), therefore data are read-across from the structurally analogous substance 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8). These substances hydrolyse at similar rate to 4 moles or 3 moles of trimethylsilanol. The non-silanol hydrolysis product, (poly)silicic acid and methylsilanetriol, is not expected to be relevant for this endpoint. Moreover, they have similar physico-chemical properties. Thus, both substances are expected to have similar toxicity profiles.

7.       AE 2.4 Exposure to other compounds than to those linked to the prediction

The target substance, 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane (CAS 3555-47-3), has a named impurity at 5-20%: 1,1,1,5,5,5-Hexamethyl-3-[(trimethylsilyl)oxy]-3-trisiloxanyl tris(trimethylsilyl) orthosilicate (CAS 18602-90-9 and synonym of Q2M6 or M6Q2). No toxicological data are available for M6Q2 however based on the weight of evidence for linear and branched siloxanes acute toxicity is not expected (PFA, 2013u). The source substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), does not have any impurities of toxicological concern.

The test substance in the study with the source substance, 1,1,1,3,5,5,5-heptamethyl-3-[(trimethylsilyl)oxy]trisiloxane (CAS 17928-28-8), has a purity of 99.9%.

8.       AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

Not relevant.

[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

PFA (2013). Peter Fisk Associates, Mammalian toxicity of linear and branched siloxanes Analogue Report, PFA.300.002.008

Justification for classification or non-classification

Based on the available read-across information, no classification is required for acute toxicity of 1,1,1,5,5,5-hexamethyl-3,3-bis[(trimethylsilyl)oxy]trisiloxane in accordance with Regulation (EC) No 1272/2008.